In a recently completed case-control study of gastric cancer funded by the California Tobacco-Related Disease Research Program 3RT-0122), we have collected extensive questionnaire data on lifestyle factors from over 600 gastric cancers patients and an equal number of population controls. Our results showed that active smoking significantly increased the risk of gastric cancer, consistent with the conclusion of several recent reviews on smoking and gastric cancer development. However, the precise mechanism by which tobacco smoke induces gastric cancer in humans is still unclear. There is increasing evidence that genetic polymorphisms in enzyme systems including cytochrome P450 CYP1A1 (CYP1A1), myloperoxidase (MPO) and glutathione S-transferases (GSTs) are involved in the metabolism of tobacco carcinogens and influence the risks of lung and bladder cancers. We hypothesize that these polymorphic genes also play a role in determining a smokers' risk of gastric cancer. To investigate the roles of a series of tobacco-carcinogen-metabolizing genes in influencing gastric cancer risk, we will use materials and information collected from our case-control study on gastric cancer (3RT-0122). Buffy coats were collected from 350 gastric cancer cases and 450 age-, sex- and race-matched population controls. We are seeking support to process these buffy coats and DNA extraction and subsequent genotyping assays on extracted DNA. Specifically, we will test the hypotheses that the risk of gastric cancer is increased among individuals who: a) possess the GSTM1 null, the GSTT1 null and/or the GSTP1 GG genotypes; and b) carry mutant CYP1A1 alleles. We will also test the hypothesis that risk of gastric cancer is decreased among individuals homozygous for the mutant AA allele of the MPO gene. We will determine the independent effects of these genetic loci and their interactive effects, if any, on gastric cancer development. In addition, we will investigate if the level of smoking exposure modifies any of these gene-disease relationships.